Jan. 12, 2011 -- A new study weighs in on the debate over the relative safety of nonsteroidal anti-inflammatory medications (NSAIDs), commonly used to treat joint and muscle aches and pain.

The study, published online in the BMJ, concludes that NSAIDs significantly increase the risk of cardiovascular events in patients who take them regularly.

"These drugs have some use in the treatment of chronic pain," says Peter Jüni, MD, head of the division of clinical epidemiology at The University of Bern in Switzerland. "But they have safety issues. In the signals we saw, there was a two- to fourfold increase in the risk of myocardial infarctions [heart attacks], stroke, or cardiovascular death, and these are, clinically, considerable increases in risk."

For example, Jüni says his review found that only 25 to 50 patients would need to be treated with NSAIDs for one year to cause one additional event such as a heart attack or stroke.

Given that millions of people take these drugs, and that many of them are seniors -- members of a group already likely to have other risk factors for heart disease -- that relatively small number needed to harm, as epidemiologists call it, is alarming to doctors.

"There's a very large overlap between cardiovascular risk and the musculoskeletal symptoms that people take NSAIDs for," says Wayne A. Ray, PhD, director of the division of pharmacoepidemiology in the department of preventive medicine at Vanderbilt University in Nashville.

A 2002 analysis of the government's National Health and Nutrition Examination Survey, for example, found that 40% of adults with osteoarthritis, or OA, also had high blood pressure, while 32% percent had high total cholesterol. Twenty percent of people with OA reported that they smoked.

"You have an 80-year-old person with a history of heart disease who has a problem with her knees. This is someone who's at cardiovascular risk and likely to be taking NSAIDs," says Wayne, who wrote an editorial that accompanied the study.

Many doctors already exercise caution when considering NSAIDs for the relief of chronic pain because these drugs are also known to increase the risk of ulcers and serious bleeding in the stomach and gastrointestinal tract.

It wasn't until relatively recently, after a study found that the painkiller Vioxx was associated with significant increases in the risks of heart attacks and strokes, that doctors started to wonder if other drugs in this class might have heart risks, too. Vioxx was taken off the market in 2004.

"We found, almost inadvertently, that these drugs can have cardiovascular effects. We were sort of caught without sufficient knowledge base to guide clinical practices," Ray says.

"There are differences in the various NSAIDs and these differences might well confer differences in cardiovascular risk. We really have less information than we need about the comparative safety of these drugs," he says.

Measuring Heart Risks in NSAIDs

For the study, Swiss researchers pooled data from 31 randomized, controlled trials, which are considered the "gold standard" of scientific evidence. The trials included more than 116,000 patients.

The study also made use of innovative statistical methods that allowed researchers to compare the relative safety of different NSAID medications, even if they'd never gone head-to-head in the same clinical trial.

The medications, which are part of the NSAID class of medications, include many names familiar to American medicine cabinets, including ibuprofen, naproxen, diclofenac (Cataflam, Voltaren) and Celebrex.

In addition, researchers looked at the relative cardiovascular risks associated with three other drugs not sold in the U.S., including Vioxx, Arcoxia, and Prexige. Those drugs, structurally similar to Celebrex, are part of a special subset of the NSAID class known as Cox-2 inhibitors.

Overall, naproxen appeared to have the safest cardiovascular risk profile of the seven included in the review.

Compared to placebos, Vioxx and Prexige were associated with twice the risk of heart attack.

Ibuprofen was associated with more than three times the risk of stroke, compared to a placebo. Diclofenac was associated with almost four times the risk of cardiovascular death.

Choosing a Safer Pain Reliever

To complicate the picture, several recent studies have also suggested that opioid pain medications, which doctors have increasingly turned to as alternatives to NSAIDs in older patients at risk for stomach or kidney problems, may also have unappreciated heart risks.

A study published in the Dec. 15/27, 2010, issue of the Archives of Internal Medicine found that opioid users had an elevated risk of having a heart attack compared to users of NSAIDs. The same study found that opioid users had higher risks of fractures than those taking NSAIDs.

"It is a big problem," Jüni says. "It just points out that we don't have a good pharmacological alternative to treat musculoskeletal pain."

Weighing the Risks and Benefits of Pain Medications

So what's the safest way to treat musculoskeletal pain?

Experts say weight loss and exercise should be a person's first line of defense against many kinds of aches and pains in joints and muscles.

If those lifestyle changes aren't enough, however, experts suggest that patients work closely with their doctors to find the safest possible medication to get the job done.

Many think that topical treatments, like NSAID gels and patches, may relieve pain without as many adverse effects for the stomach and heart as pills. And experts say that for some patients, joint replacement surgery may be a good alternative.

If you do need NSAIDs, Jüni says it's important to use them carefully, whether they are prescription or over-the-counter.

"If you take them, don't take them regularly and not daily," he says. "And if you have to take them, ideally take them once a day and not several times a day and in dosages as low as possible."